Gestational Diabetes Mellitus Resulting From Impaired β-Cell Compensation in the Absence of FoxM1, a Novel Downstream Effector of Placental Lactogen

Zhang, Hongjie; Jia Zhang; Pope, Christine F.; Crawford, Laura A.; Vasavada, Rupangi C.; Jagasia, Shubhada M.; Gannon, Maureen
January 2010
Diabetes;Jan2010, Vol. 59 Issue 1, p143
Academic Journal
OBJECTIVE--The objectives of the study were to determine whether the cell cycle transcription factor, FoxM1, is required for glucose homeostasis and β-cell mass expansion in maternal islets during pregnancy and whether FoxM1 is essential for placental lactogen (PL)-induced β-cell proliferation. RESEARCH DESIGN AND METHODS--β-Cell mass, β-cell proliferation, and glucose homeostasis were assessed in virgin, pregnant, and postpartum mice with a pancreas-wide Foxm1 deletion (FoxM1[sup △panc]). Wild-type islets were cultured with or without PL and examined for Foxm1 induction. Transgenic mice overexpressing PL in β-cells were bred with FoxM1[sup △panc] mice, and β-cell proliferation was examined. RESULTS--Foxm1 was upregulated in maternal islets during pregnancy. In contrast to controls, β-cell proliferation did not increase in pregnant FoxM1[sup △panc] females. Mutant islets showed increased Menin and nuclear p27. FoxM1[sup △panc] females developed gestational diabetes mellitus as pregnancy progressed. After parturition, euglycemia was restored in FoxM1[sup △panc] females, but islet size was significantly reduced. Strikingly, β-cell mass was normal in postpartum FoxM1[sup △panc] pancreata due to a combination of increased β-cell size and islet neogenesis. Evidence for neogenesis included increased number of endocrine clusters, increased proportion of smaller islets, and increased neurogenin 3 or insulin expression in cells adjacent to ducts. PL induced Foxm1 expression in cultured islets, and FoxM1 was essential for PL-mediated increases in β-cell proliferation in vivo. CONCLUSIONS--FoxM1 is essential for β-cell compensation during pregnancy. In the absence of increased β-cell proliferation, neogenesis is induced in postpartum FoxM1[sup △panc] pancreata. Our results suggest that FoxM1 functions downstream of PL to mediate its effects on β-cell proliferation. Diabetes 59:143-152, 2010


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